The present invention relates to processes for the preparation of a 1,4-oxazin-2-one derivative which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of N-benzyl-3-(4-fluoro-phenyl)-1,4-oxazin-2-one which is an intermediate in the preparation of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
U.S. Pat. No. 5,719,147 describes the preparation of benzyloxazinones by a two-step process starting from an optically pure glycine derivatives. Control of process parameters (e.g. reaction time, temperature, moisture content) is necessary to prevent racemisation in these steps. With reference to Example 59 in U.S. Pat. No. 5,719,147, N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one [3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone] is prepared in several steps as follows: ##STR2##
The optically pure (S)-(4-fluorophenyl)glycine is disclosed as having been prepared by means of a four-step asymmetric synthesis process which is based upon the procedure for the asymmetric synthesis of .alpha.-amino acids described by D. A. Evans et al., J. Am. Chem. Soc., (1990) 112, 4011-4030. The complexity of this four-step process combined with the sensitive nature of the protection and double alkylation reactions to give the desired 1,4-oxazin-2-one, renders these prior art syntheses impracticable when attempted on anything other than a laboratory scale.
U.S. Pat. No. 5,668,280 describes an alternative procedure which utilizes racemic N-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-one as starting material and in a minimum of steps afforded product of high enantiomeric purity in high yield. Resolution of racemic N-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-one was achieved using (-)-3-bromocamphor-8-sulphonic acid (also referred to as (-)-3-BCS) in the presence of a racemising agent. While this is an effective method for obtaining substantially pure N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one, the use of (-)-3-BCS on a large scale is expensive. Furthermore, large quantities of (-)-3-BCS are not readily available.
It will be appreciated that chiral 3-(4-fluorophenyl)-1,4-oxazin-2-one derivatives are important intermediates for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of N-benzyl-3-(4-fluoro-phenyl)-1,4-oxazin-2-one which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
General processes and intermediates have been disclosed in the art for the preparation of 5-substituted oxazinones (see J. Chem. Soc. Perkin Trans., 1, 3587 (1994); Tetrahedron, 51, 9179 (1995); Tetrahedron Lett., 36, 7081 (1995); Bull. Chem. Soc. Jpn., 65, 2359 (1992); J. Org. Chem., 57, 5462 (1992); Tetrahedron Lett., 37, 4001 (1996)). The oxazinones prepared by these published methods have substitution at the 5-position of the oxazinone ring. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of oxazinones which are unsubstituted at the 5-position of the oxazinone ring.
Accordingly, the subject invention provides a process for the preparation of N-benzyl-3(4-fluoro-phenyl)-1,4-oxazin-2-one via a very simple, short and highly efficient synthesis.